How Does 1 + 1 = Alzheimer's? (December 20, 2012)

Monya Baker writing in Nature News Blog (December 19, 2012) opens with: "Plaques and tangles pockmark the brains of people with Alzheimer’s disease. The extracellular protein amyloid-β makes plaques, and the intracellular protein tau makes tangles, but how exactly these might kill neurons is unclear."

She then goes on to report on work presented at the annual meeting of the American Society for Cell Biology in San Francisco by George Bloom and his colleagues, from the University of Virginia, Charlottesville. Neurons exposed in vitro to amyloid-β begin mitosis but die before completing cell division.

Professor Bloom says: "The framework of the process has now been defined. We think we’ve stumbled upon one of the seminal events in the transition of healthy neurons into Alzheimer neurons." The division of the neurons failed to complete mitosis when they contained the tau protein, but if tau was absent from the cell mitosis went to completion.

On the assumption that a cell-signalling cascade may be involved Matt Seward, a graduate student in Professor Bloom's lab, investigated enzymes that transfer phosphate groups from high-energy donor molecules, such as ATP to specific substrates (kinases) that had been implicated in Alzheimer’s disease, cell-cycle regulation or tau modification. He demonstrated in his in vitro experiments that three kinases, Fyn, CaMKII and PKA, each had to be activated for the neurons to begin mitosis. Each of these kinases phosphorylates tau at a particular position. Lack of phosphate at any of them precluded mitosis when the neurons were presented with amyloid-β.

The question was them as to whether or not such a process occurred in the brain, and in an attempt to answer the question Ms Baker reports that Professor Bloom "collaborated with Eric Roberson at the University of Alabama, Birmingham, who has bred mice with an amyloid-β mutation that show learning and memory problems reminiscent of Alzhiemer’s disease. He has also crossed this mutation into mice that cannot express tau and found that although the mice still develop amyloid plaques, they do not display learning or memory problems".

Histology of the brains of the mice revealed "that neurons in brains expressing tau also expressed proteins made during cell division. In mice that lacked tau, those proteins were absent".

As Professor Bloom points out, while it's been previously suggested that "amyloid is the trigger and tau is the bullet, this is the first time anyone has started to work out the biochemistry".